Correspondence

Genetic Variation in Alcohol Dehydrogenase and Myocardial Infarction

N Engl J Med 2001; 345:221-222July 19, 2001

Article

To the Editor:

Hines et al. (Feb. 22 issue)1 report that a polymorphism of the gene encoding alcohol dehydrogenase (ADH) — namely, the slow-oxidizing allele of the ADH3 gene — in male patients who consumed moderate amounts of alcohol significantly reduced the risk of myocardial infarction. However, alcohol elimination occurs by oxidation to acetaldehyde and acetate by way of both alcohol dehydrogenase and aldehyde dehydrogenase (which is encoded by ALDH). The genes for these enzymes are polymorphic at the ADH2, ADH3, and ALDH2 loci in humans,2 and the degrees of polymorphism are different in different racial and ethnic groups.

Polymorphisms of the ADH and ALDH genes have been well studied in the Chinese population, in which the incidence of myocardial infarction is among the lowest in the world (as shown in the Monitoring Trends and Determinants in Cardiovascular Disease project of the World Health Organization).3 The fast-oxidizing ADH2*2 and ADH3*1 alleles, which encode the β₂ and γ₁ subunits of alcohol dehydrogenase, predominate in the Chinese population.4 Approximately 50 percent of Chinese persons lack the aldehyde dehydrogenase type 2 activity that is encoded by the dominant ALDH2 allele, ALDH2*2, and that is associated with the “flushing response.”5 This facial flushing and other symptoms have been thought to be a genetic deterrent to heavy drinking and alcoholism.

It is the combination of ADH and ALDH polymorphisms that determines the true rate of ethanol metabolism. Persons possessing the ADH2*2 and ADH3*1 alleles generate acetaldehyde more rapidly after alcohol consumption than persons with other alleles. Deficiency of aldehyde dehydrogenase type 2 would slow the elimination of acetaldehyde, thus slowing the overall metabolism of alcohol. The combination of such genetic polymorphisms in the ADH and ALDH genes may offer insight into the basis of genetic predisposition to myocardial infarction, especially in the Chinese population.

XinQi Dong, M.D.
Yale–New Haven Hospital, New Haven, CT 06520-8030
xinqi_dong@yahoo.com

5 References

1. 1

   Hines LM, Stampfer MJ, Ma J, et al. Genetic variation in alcohol dehydrogenase and the beneficial effect of moderate alcohol consumption on myocardial infarction. N Engl J Med 2001;344:549-555
   Full Text | Web of Science | Medline

2. 2

   Thomasson HR, Crabb DW, Edenberg HJ, Li TK. Alcohol and aldehyde dehydrogenase polymorphisms and alcoholism. Behav Genet 1993;23:131-136
   CrossRef | Web of Science | Medline

3. 3

   Tunstall-Pedoe H, Kuulasmaa K, Amouyel P, Arveiler D, Rajakangas AM, Pajak A. Myocardial infarction and coronary deaths in the World Health Organization MONICA Project: registration procedures, event rates, and case-fatality rates in 38 populations from 21 countries in four continents. Circulation 1994;90:583-612
   Web of Science | Medline

4. 4

   Shen YC, Fan JH, Edenberg HJ, et al. Polymorphism of ADH and ALDH genes among four ethnic groups in China and effects upon the risk for alcoholism. Alcohol Clin Exp Res 1997;21:1272-1277
   CrossRef | Web of Science | Medline

5. 5

   Muramatsu T, Wang ZC, Fang YR, et al. Alcohol and aldehyde dehydrogenase genotypes and drinking behavior of Chinese living in Shanghai. Hum Genet 1995;96:151-154
   CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: We agree that both alcohol dehydrogenase and aldehyde dehydrogenase predominantly determine the rate of ethanol metabolism. Our study involved a white population, in which variant alleles at the ADH2 and ALDH2 loci are uncommon (occurring in less than 10 percent of the population).1 Thus, it is unlikely that polymorphisms at these loci would substantially contribute to variations in metabolic capacity in white persons. Furthermore, it would take a study population considerably larger than ours to provide adequate power to investigate the role of these less common polymorphisms. Allele frequencies often depend on the race or ethnicity of the population, an indication of the importance of investigating the role of genetic variation among different groups. It would be of interest to investigate the role of ADH2 and ALDH2 polymorphisms and predisposition to myocardial infarction in Asian populations. However, the flushing response due to acetaldehyde toxicity may influence the drinking habits of persons with certain genotypes. Thus, it may be difficult to tease apart the effect of the capacity for ethanol metabolism, according to ADH and ALDH genotypes, on the risk of myocardial infarction independently of the effect of these genotypes on the amount of alcohol consumed, which would also influence the risk of myocardial infarction.

Lisa M. Hines, S.M.
Meir J. Stampfer, M.D., Dr.P.H.
David J. Hunter, M.B., B.S., Sc.D.
Channing Laboratory, Boston, MA 02115
lhines@hsph.harvard.edu

1 References

1. 1

   Bosron WF, Lumeng L, Li TK. Genetic polymorphism of enzymes of alcohol metabolism and susceptibility to alcoholic liver disease. Mol Aspects Med 1988;10:147-158
   CrossRef | Web of Science | Medline